Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study

We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P<0.05), with high alanine aminotransferase levels in Hispanics (P<0.05) and a more favorable lipoprotein profile (lower low-density lipoprotein, small dense low-density lipoprotein, and very small low-density lipoprotein) in Caucasians and Hispanics (all P<0.05). The liver biopsy showed a higher prevalence of fibrosis (P=0.04) and a higher nonalcoholic fatty liver disease activity score (P=0.05) in subjects carrying the minor allele than in those homozygous for the common allele. Moreover, we observed a joint effect among the TM6SF2 rs58542926, the PNPLA3 rs738409, and the GCKR rs1260326 SNPs in determining intrahepatic fat accumulation (P<0.05). Conclusion: The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk. (Hepatology 2016;63:117-125)